Slowing gait and difficulty walking are major and common problems of older adults, they worsen with age and they are associated with greater risk of disability, hospitalization and death. There is strong emergent evidence that structural brain abnormalities, such as white matter hyperintensities (WMH), are associated with lower- extremity mobility limitations. Our preliminary data suggest there is a striking high prevalence of 'resilient' elderly, who have preserved mobility and function despite substantial WMH. In two of our independent studies, more than 40% of individuals with substantial WMH have faster than expected mean gait, normal physical function and greater 10-year survival rate. These adults also have normal information-processing speed, a cognitive domain strongly related to mobility. We propose that this apparent resilience is related to unique neural activation patterns and to slower accrual of micro-structural abnormalities within critical mobility-related regions (Aim 1). These features are not visible on standard structural MRI obtained at one time point and require advanced longitudinal MRI methodology. Based on previous work and our pilot work we hypothesize that higher neural activation offsets the adverse impact of overall WMH on function (Aim 2). Aim 3 will explore the relationship of risk factors and resilience. In particular, we will test whether slower longitudinal worsening of risk factors (blood pressure, interleukine-6 and glucose) can enhance resilience, by slowing down the accrual of micro-structural abnormalities. Although it is known that greater cross-sectional levels of these risk factors are associated with WMH the impact of their longitudinal trajectories on brain functional and micro-structural characteristics has not been examined in large groups of older adults. In this dual-PI project, Drs. Rosano and Aizenstein propose to acquire a repeat brain MRI in older adult participants of a parent longitudinal NIA epidemiologic study - the Health ABC study (Health, Aging and Body Composition Study) ongoing since 1996. Participants have received a 1st brain MRI in 2007-08 with measures of micro-structure (PI: Dr. Rosano, K23AG028966-01, R01 AG029232). The proposed 2nd MRI will measure brain function (neural activation) in addition to micro-structure. This study cost-effectively leverages longitudinal data on cardiometabolic and inflammatory risk factors, as well as hospitalization and strokes ascertained for 14 years. While Dr. Rosano's MRI study is ongoing, it is absolutely critical to obtain a 2nd MRI to measure longitudinal microstructural changes, maximize participants' retention and minimize costs. This proposal differs from Dr. Rosano's current study of cross-sectional structural brain measures, because it will focus on functional (neural activation) and longitudinal micro-structural changes. Results from this research project may shed light on the mechanisms underlying physical disability and may help us prepare prevention and intervention studies. PUBLIC HEALTH RELEVANCE: This is a longitudinal neuroepidemiological study to identify the brain characteristics and risk factors of older adults who have maintained good mobility in the face of substantial structural brain abnormalities. Cutting-edge neuroimaging and epidemiological methods are applied.